Certificate of correction



Uited atent 3,055,893 Patented Sept. 25, 1962 This invention relates to 4-[l-carboxy-l,2,3,4,4a,9,10, IOa-octahydro 1,4a dimethyl-9-oxo-6-oxy-7-phenanthrene(acyl/thionoacyl)]morpholines, esters correspond ing, and processes for the manufacture thereof. More particularly, this invention relates to chemical compounds of the formula RI! wherein R and R" each represent hydrogen or an alkyl radical, .Alk represents an alkylene radical, n represents or the positive integer 1, and X represents oxygen or sulfur.

Among the alkyl radicals represented by R and R", especially lower alkyl radicals are preferred, illustratively methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tertbutyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, and homologous groupings embracive of fewer than 9 carbon atoms.

The alkylene radicals comprehended by Alk are likewise optimally of lower order, for example, methylene, ethylene, trimethylene, propylene, tetrarnethylene, pentylene, and such other bivalent saturated acyclic straight or branched-chain hydrocarbon groupings as may be thought of as derived from a lower alkyl radical by removal of 1 atom of hydrogen.

Those skilled in the art will appreciate that when n in the foregoing formula represents 0 the Alk term drops out and the morpholines represented are 7-phenanthrene (carboxylic/thionocarboxylic) acid derivatives.

The compounds to which this invention relates are useful because of their valuable pharmacological properties. Thus, for example, they are antibiotics adapted to inhibit the growth of bacteria such as E. coli; and they are diuretics characterized by a capacity to block the effect of desoxycorticosterone acetate on urinary sodium and potassium. They are also anti-androgens.

Manufacture of the subject compounds proceeds by oxidation in an inert medium with chromium trioxide and an acid such as acetic or sulfuric of a corresponding 9-methylenic compound in the formula of which R, R", defined as before.

which result are converted ad libitum to phenanthrenethionoacylmorpholines by heating with phosphorus pentasulfide in benzene solution, the product being isolated by chromatography on silica gel.

Alternatively, the compounds of this invention are manufactured via the Kindler modification of the Willgerodt procedure as applied to 7-carbonylphenanthrenes of the formula wherein R, R", Alk, and n have the same meanings assigned above, the phenanthrenethionoacylmorpholines thus obtained being converted to phenanthreneacylmorpholines as desired by contacting with chromium trioxide and a suitable acid in an inert medium.

From the 1 carboxyphenanthreneacylmorpholines hereof are produced corresponding esters by heating with a dialkyl sulfate and an alkali metal hydroxide in a lower alkanol.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for their manufacture. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth, temperatures are given in degrees centigrade and relative amounts of materials in parts by weight, except as otherwise noted. Specific rotations are at 25 C. referred to the D line of sodium.

Example 1 4 (1,2,3,4,4a,9,10,10a octahydro 6 methoxy 1- methoxycarbonyl 1,4a dimethyl 9 oxo 7 phenanthreneacetyl)-m0rph0line.-To a mixture of 10 parts of 4 (1,2,3,4,4a,9,10,l0a octahydro 6 methoxy l methoxycarbonyl 1,4a dimethyl 7 phenanthrenethionacetyl)morpholine and parts of acetone is added, with agitation at room temperatures during 30 minutes, a solution of 7 parts of chromium trioxide dissolved in 12 parts of water diluted with 10 parts of concentrated sulfuric acid. When the addition is complete, approximately 10 volumes of water is incorporated; and the solid precipitate thrown down is collected on a filter and recrystallized from a mixture of acetone and hexane. The 4 (l,2,3,4,4a,9,l0,l0a octahydro 6 methoxy 1- methoxycarbonyl 1,4a dimethyl 9 oxo 7 phenanthreneacetyDmorpholine thus obtained melts at 218.5- 220". It has the formula Example 2 4-(1 ethoxycarbonyl 1,2,3,4,4a,9,10,10a octahydro- 6 methoxy 1,4a dimethyl 9 x0 7 phenanthreneacetyl)m0rph0line.--Substitution of parts of 4 (1 ethoxycarbonyl 1,2,3,4,4a,9,10,10a octahydro- 6 methoxy 1,4a dimethyl 7 phenanthreneacetyD- morpholine for the 4-(l-methoxycarbonyl-l,2,3,4,4a,9,10, 10a octahydro 6 methoxy 1,4a dimethyl 7 phenanthrenethionoacetyl)morpholine called for in Example 1 affords, by the procedure there detailed, 4-(1-ethoxycarbonyl 1,2,3,4,4a,9,10,10a octahydro 6 mehoxy- 1,4a-dimethyl-9-oxo-7 phenanthreneacetyl) morpholine of the formula CH; -o 0 0 01m o=( 0 OH; ll 0 N-O-CHz- (SCH:

Example 3 4 (6 ethoxy 1 ethoxycarbonyl 1,2,3,4,4a,9,10, 10a octahydro 1,4a dimethyl 9 0x0 7 phenanthreneacetyl)m0rph0line.--Substitution of 10 parts of 4- (6 ethoxy 1 ethoxycarbonyl l,2,3,4,4a,9,10,10aoctahydro 1,4a dimethyl-7-phenanthrenethionoacetyl)- morpholine for the 4-(1,2,3,4,4a,9,10,1021-octahydro-6- methoxy 1 methoxycarbonyl 1,4a dimethyl-7-phenanthrenethionoacetyl)morpholine called for in Example 1 affords, by the procedure there detailed, 4-(6-ethoxy-1- ethoxycarbonyl 1,2,3,4,4a,9,10,10a octahydro 1,4adimethyl 9 oxo 7 phenanthreneacetyl)morpholine. The product has the formula OOOCrH;

O CH: ll 0 N CHT Example 4 4-(1,2,3,4,4a,9,10,10a octahydro 6 methoxy 1- methoxycarbonyl 1,4a dimethyl 9 0x0 7 phenanthrenepropionyl)m0rpholine.-To a slurry of 15 parts of 4 (1,2,3,4,4a,9,10,10a octahydro 6 methoxy-lmethoxycarbonyl 1,4a dimethyl 7 phenanthrenethionopropionyl)morpholine in 160 parts of acetic acid and parts of water at 9-13 is added, with agitation during 1 hour, 13 parts of chromium trioxide dissolved in 7 parts of water diluted with 13 parts of acetic acid. The resultant mixture is let stand overnight at room temperatures and then diluted with 1000 parts of aqueous 5% ethanol. The mixture thus obtained is distilled to /2 its original volume and then extracted with ether. The ether extract is successively washed with Water, aqueous 10% sodium hydroxide, and water, following which it is dried over anhydrous sodium sulfate and finally stripped of solvent by distillation. The light yellow solid residue is taken up in benzene, and the benzene solution is chromatographed on silica gel, using benzene and ethyl acetate as developing solvents. From the eluate comprising 4 50% ethyl acetate in benzene is obtained 4'(1,2,3,4,4a, 9,10,10a octahydro 6 methyl 1 methoxycarbonyl- 1,4a dimethyl 9 oxo 7 phenanthrenepropionyl)- morpholine which, recrystallized from aqueous methanol, melts at 153-1545". The product has the formula on, 'o o 0 on; of O OH: i5 0 N CH2CH2- Example 5 CO OH CH3 ll 0 NCCHZCH2 Example 6 4 (1,2,3,4,4a,9,10,10a octahydro 6 methoxy-lmethoxycarbonyl 1,4a dimethyl-9-oxo-7-phemmthrenethionoacetyl)m0rph0line.-A mixture of 25 parts of 7- acetyl-l,2,3,4,4a,9,10,10a-octahydro-6-methoxy 1 methoxycarbonyl-l,4a-dimethyl-9-oxophenanthrene, 2 parts of sulfur, and 6 parts of morpholine is heated at approximately 150 for 10 hours. The resulting mixture is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and ethyl acetate as developing solvents. From eluates comprising 15% ethyl acetate and benzene, on evaporation of solvent, there is obtained 4 (1,2,3,4,4a,9,10,10a octahydro-6- methoxy-l-methoxycarbonyl 1,4a dimethyl-9-oxo-7- phenanthrenethionoacetyl) morpholine as the residue which, recrystallized from aqueous methanol, melts at 180.5183.5 and is further characterized by a specific rotation of +57. The product has the formula What is claimed is: 1. A compound of the formula wherein R is selected from the group consisting of hydrogen and alkyl radicals of the formula in which m is a positive integer less than 9, R" is an alkyl radical of the formula in which in has the same meaning assigned above, Alk is an alkylene radical of the formula in which in again has the same meaning assigned above, and X is selected from the group consisting of oxygen and sulfur.

2. A compound of the formula wherein R and R" are alkyl radicals of the formula and Alk is an alkylene radical of the formula m and m being positive integers less than 9,

3. A compound of the formula 4) CH3 wherein R is an alkyl radical of the formula m 2m+1 and Alk is an alkylene radical of the formula m 2m' m and m being positive integers less than 9.

4. A compound of the formula oooom wherein Alk is an alkylene radical of the formula References Cited in the file of this patent UNITED STATES PATENTS 2,901,487 Elpern Aug. 25, 1959 2,902,494 Bible Sept. 1, 1959 2,921,956 Bible Jan. 19 1960 2,947,778

Bible Aug. 2, 1960 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent Non 3,055,893 September 25, 1962 Roy H. Bible, Jr.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 47, for "threneacetyDmorpholine", in italics read threneacetyDmorpholine in italcis; line 59, for "-9 oxo read 9ox0 column 3, line 12, for "-mehoxyread methoxyline 13, for "phenanthrene acetyD-morpholine" read phenanthreneacetyl)morpholine column 4, line 2, for "6methyl" read 6methoxy* line 21, for "-phenanthrenepropionyl)-morpho", in italics, read -phenanthrenepropionyl)morpho in italics; line 26, for "'phenanthrenethionopropionyl) read -phenanthrenethionopropionyl) column 6, line 37, a for "acetyl) morpholi.ne" read acetyDmorpholine line 40, for propionyD morpholine" read propionyDmorpholine Signed and sealed this 7th day of January 1964.

(SEAL) Attest: is I r,

ERNEST W. SWIDER EDWIN L. REYNOLDS Acting Commissioner Attesting Officer of Patents 

1. A COMPOUND OF THE FORMULA
 2. A COMPOUND OF THE FORMULA 